Full Text Journal Articles by
Author Agnieszka K Witkiewicz

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Phase I Clinical Trial of Combination Propranolol and Pembrolizumab in Locally Advanced and Metastatic Melanoma: Safety, Tolerability, and Preliminary Evidence of Antitumor Activity.

Shipra Gandhi, Manu R Pandey, Kristopher Attwood, Wenyan Ji, Agnieszka K Witkiewicz, Erik S Knudsen, Cheryl Allen, Joseph D Tario, Paul K Wallace, Carlos D Cedeno, Maria Levis, Suzanne Stack, Pauline Funchain, Joseph J Drabick, Mark J Bucsek, Igor Puzanov, Hemn Mohammadpour, Elizabeth A Repasky, Marc S Ernstoff,

PURPOSE:Increased β-adrenergic receptor (β-AR) signaling has been shown to promote the creation of an immunosuppressive tumor microenvironment (TME). Preclinical studies have shown that abrogation of this signaling pathway, particularly β2-AR, provides a more favorable TME that enhances the activity of anti-PD-1 checkpoint inhibitors. We hypothesize that blocking stress-related immunosuppressive pathways ... Read more >>

Clin Cancer Res (Clinical cancer research : an official journal of the American Association for Cancer Research)
[2020, :]

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Metabolic Reprogramming of Pancreatic Cancer Mediated by CDK4/6 Inhibition Elicits Unique Vulnerabilities.

Jorge Franco, Uthra Balaji, Elizaveta Freinkman, Agnieszka K Witkiewicz, Erik S Knudsen,

Cell Rep (Cell reports)
[2020, 32(1):107793]

Cited: 0 times

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A Phase I Study of Ribociclib Plus Everolimus in Patients with Metastatic Pancreatic Adenocarcinoma Refractory to Chemotherapy.

Benjamin A Weinberg, Hongkun Wang, Agnieszka K Witkiewicz, John L Marshall, Aiwu R He, Paris Vail, Erik S Knudsen, Michael J Pishvaian,

Purpose: Metastatic pancreatic adenocarcinoma (mPC) has a poor prognosis. CDK4/6 is often deregulated in mPC due to CDKN2A loss, resulting in the loss of p16INK4a that inhibits CDK4/6. CDK4/6 inhibitor monotherapy is ineffective due to RAS-mediated activation of alternative pathways, including phosphatidylinositol 3-kinase-mammalian target of rapamycin (PI3K-mTOR). We conducted a ... Read more >>

J Pancreat Cancer (Journal of pancreatic cancer)
[2020, 6(1):45-54]

Cited: 0 times

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Chemotherapy and CDK4/6 Inhibitors: Unexpected Bedfellows.

Patrick J Roberts, Vishnu Kumarasamy, Agnieszka K Witkiewicz, Erik S Knudsen,

Cyclin-dependent kinases 4 and 6 (CDK4/6) have emerged as important therapeutic targets. Pharmacologic inhibitors of these kinases function to inhibit cell-cycle progression and exert other important effects on the tumor and host environment. Because of their impact on the cell cycle, CDK4/6 inhibitors (CDK4/6i) have been hypothesized to antagonize the ... Read more >>

Mol. Cancer Ther. (Molecular cancer therapeutics)
[2020, 19(8):1575-1588]

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Chronic expression of p16INK4a in the epidermis induces Wnt-mediated hyperplasia and promotes tumor initiation.

Narmen Azazmeh, Benjamin Assouline, Eitan Winter, Shmuel Ruppo, Yuval Nevo, Alexander Maly, Karen Meir, Agnieszka K Witkiewicz, Jonathan Cohen, Sophia V Rizou, Eli Pikarsky, Chen Luxenburg, Vassilis G Gorgoulis, Ittai Ben-Porath,

p16INK4a (CDKN2A) is a central tumor suppressor, which induces cell-cycle arrest and senescence. Cells expressing p16INK4a accumulate in aging tissues and appear in premalignant lesions, yet their physiologic effects are poorly understood. We found that prolonged expression of transgenic p16INK4a in the mouse epidermis induces hyperplasia and dysplasia, involving high ... Read more >>

Nat Commun (Nature communications)
[2020, 11(1):2711]

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Targeting dual signalling pathways in concert with immune checkpoints for the treatment of pancreatic cancer.

Erik S Knudsen, Vishnu Kumarasamy, Sejin Chung, Amanda Ruiz, Paris Vail, Stephanie Tzetzo, Jin Wu, Ram Nambiar, Jared Sivinski, Shailender S Chauhan, Mukund Seshadri, Scott I Abrams, Jianmin Wang, Agnieszka K Witkiewicz,

OBJECTIVE:This study exploits the intersection between molecular-targeted therapies and immune-checkpoint inhibition to define new means to treat pancreatic cancer. DESIGN:Patient-derived cell lines and xenograft models were used to define the response to CDK4/6 and MEK inhibition in the tumour compartment. Impacts relative to immunotherapy were performed using subcutaneous and orthotopic ... Read more >>

Gut (Gut)
[2020, :]

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Author Correction: Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer.

Kirsten L Bryant, Clint A Stalnecker, Daniel Zeitouni, Jennifer E Klomp, Sen Peng, Andrey P Tikunov, Venugopal Gunda, Mariaelena Pierobon, Andrew M Waters, Samuel D George, Garima Tomar, Björn Papke, G Aaron Hobbs, Liang Yan, Tikvah K Hayes, J Nathaniel Diehl, Gennifer D Goode, Nina V Chaika, Yingxue Wang, Guo-Fang Zhang, Agnieszka K Witkiewicz, Erik S Knudsen, Emanuel F Petricoin, Pankaj K Singh, Jeffrey M Macdonald, Nhan L Tran, Costas A Lyssiotis, Haoqiang Ying, Alec C Kimmelman, Adrienne D Cox, Channing J Der,

An amendment to this paper has been published and can be accessed via a link at the top of the paper. ... Read more >>

Nat Med (Nature medicine)
[2020, 26(6):982]

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Pan-cancer molecular analysis of the RB tumor suppressor pathway.

Erik S Knudsen, Ram Nambiar, Spencer R Rosario, Dominic J Smiraglia, David W Goodrich, Agnieszka K Witkiewicz,

The retinoblastoma tumor suppressor gene (RB1) plays a critical role in coordinating multiple pathways that impact cancer initiation, disease progression, and therapeutic responses. Here we probed molecular features associated with the RB-pathway across 31 tumor-types. While the RB-pathway has been purported to exhibit multiple mutually exclusive genetic events, only RB1 ... Read more >>

Commun Biol (Communications biology)
[2020, 3(1):158]

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p27 allosterically activates cyclin-dependent kinase 4 and antagonizes palbociclib inhibition.

Keelan Z Guiley, Jack W Stevenson, Kevin Lou, Krister J Barkovich, Vishnu Kumarasamy, Tilini U Wijeratne, Katharine L Bunch, Sarvind Tripathi, Erik S Knudsen, Agnieszka K Witkiewicz, Kevan M Shokat, Seth M Rubin,

The p27 protein is a canonical negative regulator of cell proliferation and acts primarily by inhibiting cyclin-dependent kinases (CDKs). Under some circumstances, p27 is associated with active CDK4, but no mechanism for activation has been described. We found that p27, when phosphorylated by tyrosine kinases, allosterically activated CDK4 in complex ... Read more >>

Science (Science (New York, N.Y.))
[2019, 366(6471):]

Cited: 3 times

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Chemotherapy impacts on the cellular response to CDK4/6 inhibition: distinct mechanisms of interaction and efficacy in models of pancreatic cancer.

Vishnu Kumarasamy, Amanda Ruiz, Ram Nambiar, Agnieszka K Witkiewicz, Erik S Knudsen,

Pancreatic ductal adenocarcinoma (PDAC) is a therapy recalcitrant disease characterized by the aberrations in multiple genes that drive pathogenesis and limit therapeutic response. While CDK4/6 represents a downstream target of both KRAS mutation and loss of the CDKN2A tumor suppressor in PDAC, clinical and preclinical studies indicate that pharmacological CDK4/6 ... Read more >>

Oncogene (Oncogene)
[2020, 39(9):1831-1845]

Cited: 4 times

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Interrogating Mutant Allele Expression via Customized Reference Genomes to Define Influential Cancer Mutations.

Adam D Grant, Paris Vail, Megha Padi, Agnieszka K Witkiewicz, Erik S Knudsen,

Genetic alterations are essential for cancer initiation and progression. However, differentiating mutations that drive the tumor phenotype from mutations that do not affect tumor fitness remains a fundamental challenge in cancer biology. To better understand the impact of a given mutation within cancer, RNA-sequencing data was used to categorize mutations ... Read more >>

Sci Rep (Scientific reports)
[2019, 9(1):12766]

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Cell Cycle and Beyond: Exploiting New RB1 Controlled Mechanisms for Cancer Therapy.

Erik S Knudsen, Steven C Pruitt, Pamela A Hershberger, Agnieszka K Witkiewicz, David W Goodrich,

Recent studies highlight the importance of the RB1 tumor suppressor as a target for cancer therapy. Canonically, RB1 regulates cell cycle progression and represents the downstream target for cyclin-dependent kinase (CDK) 4/6 inhibitors that are in clinical use. However, newly discovered features of the RB1 pathway suggest new therapeutic strategies ... Read more >>

Trends Cancer (Trends in cancer)
[2019, 5(5):308-324]

Cited: 10 times

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Cell cycle plasticity driven by MTOR signaling: integral resistance to CDK4/6 inhibition in patient-derived models of pancreatic cancer.

Erik S Knudsen, Vishnu Kumarasamy, Amanda Ruiz, Jared Sivinski, Sejin Chung, Adam Grant, Paris Vail, Shailender S Chauhan, Tun Jie, Taylor S Riall, Agnieszka K Witkiewicz,

Pancreatic ductal adenocarcinoma (PDAC), like many KRAS-driven tumors, preferentially loses CDKN2A that encodes an endogenous CDK4/6 inhibitor to bypass the RB-mediated cell cycle suppression. Analysis of a panel of patient-derived cell lines and matched xenografts indicated that many pancreatic cancers have intrinsic resistance to CDK4/6 inhibition that is not due ... Read more >>

Oncogene (Oncogene)
[2019, 38(18):3355-3370]

Cited: 5 times

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Correction: Kinome-Wide RNA Interference Screen Reveals a Role for PDK1 in Acquired Resistance to CDK4/6 Inhibition in ER-Positive Breast Cancer.

Valerie M Jansen, Neil E Bhola, Joshua A Bauer, Luigi Formisano, Kyung-Min Lee, Katherine E Hutchinson, Agnieszka K Witkiewicz, Preston D Moore, Mónica Valéria Estrada, Violeta Sánchez, Paula G Ericsson, Melinda E Sanders, Paula R Pohlmann, Michael J Pishvaian, David A Riddle, Teresa C Dugger, Wenyi Wei, Erik S Knudsen, Carlos L Arteaga,

Cancer Res (Cancer research)
[2019, 79(4):874]

Cited: 0 times

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Coordinately Targeting Cell-Cycle Checkpoint Functions in Integrated Models of Pancreatic Cancer.

Sejin Chung, Paris Vail, Agnieszka K Witkiewicz, Erik S Knudsen,

PURPOSE:Cancer cells often have deficiencies in cell-cycle control mechanisms and could be dependent on specific cell-cycle checkpoints to maintain viability. Because of the documented role of KRAS in driving replication stress, we targeted the checkpoint governing DNA replication using CHK1 kinase inhibitors in pancreatic ductal adenocarcinoma (PDAC) models and examined ... Read more >>

Clin Cancer Res (Clinical cancer research : an official journal of the American Association for Cancer Research)
[2019, 25(7):2290-2304]

Cited: 6 times

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Targeting the Vulnerability of RB Tumor Suppressor Loss in Triple-Negative Breast Cancer.

Agnieszka K Witkiewicz, Sejin Chung, Rachel Brough, Paris Vail, Jorge Franco, Christopher J Lord, Erik S Knudsen,

Approximately 30% of triple-negative breast cancers (TNBCs) exhibit functional loss of the RB tumor suppressor, suggesting a target for precision intervention. Here, we use drug screens to identify agents specifically antagonized by the retinoblastoma tumor suppressor (RB) using CDK4/6 inhibitors. A number of candidate RB-synthetic lethal small molecules were identified, ... Read more >>

Cell Rep (Cell reports)
[2018, 22(5):1185-1199]

Cited: 11 times

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Composite analysis of immunological and metabolic markers defines novel subtypes of triple negative breast cancer.

Thomas A Adams, Paris J Vail, Amanda Ruiz, Mehri Mollaee, Peter A McCue, Erik S Knudsen, Agnieszka K Witkiewicz,

Cancer biology is influenced by the tumor microenvironment, which impacts disease prognosis and therapeutic interventions. The inter-relationship of tumor-infiltrating lymphocytes, immune response regulators, and a glycolytic tumor environment was evaluated in a cohort of 183 largely consecutive patients with triple negative breast cancer diagnosis. High levels of tumor-infiltrating lymphocytes were ... Read more >>

Mod Pathol (Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc)
[2018, 31(2):288-298]

Cited: 8 times

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Sampling strategies to capture single-cell heterogeneity.

Satwik Rajaram, Louise E Heinrich, John D Gordan, Jayant Avva, Kathy M Bonness, Agnieszka K Witkiewicz, James S Malter, Chloe E Atreya, Robert S Warren, Lani F Wu, Steven J Altschuler,

Advances in single-cell technologies have highlighted the prevalence and biological significance of cellular heterogeneity. A critical question researchers face is how to design experiments that faithfully capture the true range of heterogeneity from samples of cellular populations. Here we develop a data-driven approach, illustrated in the context of image data, ... Read more >>

Nat Methods (Nature methods)
[2017, 14(10):967-970]

Cited: 5 times

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The transcriptome of CDK4/6 inhibition.

Erik S Knudsen, Agnieszka K Witkiewicz,

Aging (Albany NY) (Aging)
[2017, 9(8):1859-1860]

Cited: 1 time

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Biological specificity of CDK4/6 inhibitors: dose response relationship, in vivo signaling, and composite response signature.

Erik S Knudsen, Jack Hutcheson, Paris Vail, Agnieszka K Witkiewicz,

Recently developed potent and selective CDK4/6 inhibitors fall into two classes based on structure and toxicity profiles in clinical studies. One class, exemplified by palbociclib and ribociclib, exhibits neutropenia as a dose-limiting toxicity and requires discontinuous dosing. In contrast, the structurally distinct CDK4/6 inhibitor abemaciclib is dosed continuously, and has ... Read more >>

Oncotarget (Oncotarget)
[2017, 8(27):43678-43691]

Cited: 16 times

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Stratification of Pancreatic Ductal Adenocarcinoma: Combinatorial Genetic, Stromal, and Immunologic Markers.

Erik S Knudsen, Paris Vail, Uthra Balaji, Hoai Ngo, Ihab W Botros, Vladimir Makarov, Nadeem Riaz, Vinod Balachandran, Steven Leach, Debrah M Thompson, Timothy A Chan, Agnieszka K Witkiewicz,

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is associated with an immunosuppressive milieu that supports immune system evasion and disease progression. Here, we interrogated genetic, stromal, and immunologic features of PDAC to delineate impact on prognosis and means to more effectively employ immunotherapy.Experimental Design: A cohort of 109 PDAC cases annotated for ... Read more >>

Clin Cancer Res (Clinical cancer research : an official journal of the American Association for Cancer Research)
[2017, 23(15):4429-4440]

Cited: 37 times

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Kinome-Wide RNA Interference Screen Reveals a Role for PDK1 in Acquired Resistance to CDK4/6 Inhibition in ER-Positive Breast Cancer.

Valerie M Jansen, Neil E Bhola, Joshua A Bauer, Luigi Formisano, Kyung-Min Lee, Katherine E Hutchinson, Agnieszka K Witkiewicz, Preston D Moore, Mónica Valéria Estrada, Violeta Sánchez, Paula G Ericsson, Melinda E Sanders, Paula R Pohlmann, Michael J Pishvaian, David A Riddle, Teresa C Dugger, Wenyi Wei, Erik S Knudsen, Carlos L Arteaga,

Acquired resistance to cyclin-dependent kinases 4 and 6 (CDK4/6) small-molecule inhibitors in breast cancer arises through mechanisms that are yet uncharacterized. In this study, we used a kinome-wide siRNA screen to identify kinases that, when downregulated, yield sensitivity to the CDK4/6 inhibitor ribociclib. In this manner, we identified 3-phosphoinositide-dependent protein ... Read more >>

Cancer Res (Cancer research)
[2017, 77(9):2488-2499]

Cited: 57 times

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Pancreatic cancer cell lines as patient-derived avatars: genetic characterisation and functional utility.

Erik S Knudsen, Uthra Balaji, Brian Mannakee, Paris Vail, Cody Eslinger, Christopher Moxom, John Mansour, Agnieszka K Witkiewicz,

Pancreatic ductal adenocarcinoma (PDAC) is a therapy recalcitrant disease with the worst survival rate of common solid tumours. Preclinical models that accurately reflect the genetic and biological diversity of PDAC will be important for delineating features of tumour biology and therapeutic vulnerabilities.27 primary PDAC tumours were employed for genetic analysis ... Read more >>

Gut (Gut)
[2018, 67(3):508-520]

Cited: 24 times

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The Strange Case of CDK4/6 Inhibitors: Mechanisms, Resistance, and Combination Strategies.

Erik S Knudsen, Agnieszka K Witkiewicz,

CDK4/6 inhibitors have emerged as a powerful class of agents with clinical activity in a number of malignancies. Targeting the cell cycle represents a core attack on a defining feature of cancer. However, the mechanisms through which selective CDK4/6 targeted agents act has few parallels in the current pharmaceutical armamentarium ... Read more >>

Trends Cancer (Trends in cancer)
[2017, 3(1):39-55]

Cited: 47 times

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Defining the transcriptional and biological response to CDK4/6 inhibition in relation to ER+/HER2- breast cancer.

Erik S Knudsen, Agnieszka K Witkiewicz,

ER positive (ER+) and HER2 negative (HER2-) breast cancers are routinely treated based on estrogen dependence. CDK4/6 inhibitors in combination with endocrine therapy have significantly improved the progression-free survival of patients with ER+/HER2- metastatic breast cancer. Gene expression profiling in ER+/HER2- models was used to define the basis for the ... Read more >>

Oncotarget (Oncotarget)
[2016, 7(43):69111-69123]

Cited: 14 times

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